Molly McGovern Chair in Biomedical Research
There are a variety of rotation projects that use a variety of imaging and biochemical techniques to assess microglial function in the CNS. The main projects are highlighted below. 1. Dissecting novel molecular mechanisms underlying microglial function at synapses. 2. Exploring new roles for microglia in the spread of neuroinflammation in neurological disease. 3. Identifying novel ways microglia regulate other glial cell populations (astrocytes and oligodendrocytes) in the CNS.
Psychology Department and Center for Neuroendocrin
Department of Psychology; Neuroscience And Behavio
Psychology And Neuroscience & Behavior Program
Psychology Department And Center for Neuroendocrin
Health Informatics And Implementation Science
Elisabeth Chair for the Dean of Medicine
Cutler Chair in Vascular and Endovascular Surgery
Penelope Booth Rockwell Chair in Biomedical Research
Focus: Adeno-associated virus vector mediated gene transfer for gene therapy, gene therapy of inherited neurodegenerative Canavan Disease
Dr. Esteves is a neuroscientist with interest in gene therapy to help treat neurodegenerative diseases.
An entry level postdoctoral position is open immediately in the laboratory of Dr. Susan L. Swain to study the factors that control the development and survival of CD4 and CD8 T cell memory. Graduate student experience with tissue culture, in vitro assay, flow cytometry, experience in mouse models on infectious disease and a knowledge of cellular and molecular immunology are all strongly desired.
<p >Rotations: Projects in the following areas <p >CD4 T cell memory. We can generate in vitro CD4 T cells that are for all extents and purposes identical to the memory CD4 T cells observed in vivo. In situ memory CD4 T cells persist at very low frequency and in most instances it is difficult to analyze them thoroughly using tetramer or multimer reagents both because of their low frequency and the relatively low specific affinity of the Class II reagents for the TcR. Being able to generate “recent” memory cells in vitro gives us the opportunity to analyze in detail the mechanisms by which memory CD4 T cells may contribute to secondary immunity and immune protection. Once identified. will determine if particular pathways are relevant in situ. We have discovered that memory CD4 T cells are superior in protection to those from the primary response and that they display pleitropic functions that have not been previously identified. <p > Cytotoxic CD4 Effectors. One unexpected function of CD4 T cells we identified is robust, perforin-dependent cytotoxic activity (7, 16). Cytotoxic activity by CD4 T cells has been reported in response to several infections, but its significance has not heretofore been established. We find that “Th1 polarized” CD4 effectors and more relevantly the CD4 effectors found in the lung following influenza infection, are able to kill infected or peptide-pulsed Class II-bearing targets and we find that this perforin dependent activity can work together with antibody to provide protection against lethal influenza challenge in otherwise unprimed mice (17). We also will determine when memory CD4 T cells re-express cytotoxic activity following in vivo challenge and how cytotoxic killing contributes to the memory cell mediated protection. We want to analyze how the program of cytotoxicity is induced in these “ThCTL”. <p > Memory CD4 Cells Enhance an Innate Response. Memory cells can act by becoming secondary effectors but they are best characterized by their ability respond rapidly even to low antigen doses, by producing cytokines and chemokines and it is assumed that these initial abilities are key to memory cell activity. However this assumption has not been directly demonstrated and the mechanisms involved and how they might contribute to immunity have not been elucidated. We find that restimulation of memory CD4 T cells leads to a markedly enhanced early innate response to influenza infection both in the lung and systemically (17). This response peaks 2-3 days after infection and is transient. We see enhanced production of IL-6 locally and systemically and enhanced production a broad spectrum of innate inflammatory mediators in the lung. We hope to determine in detail the pathways leading to optimum memory T cell-induced innate responses. We suggest a concurrent activation of CD4 memory cells may be an effective adjuvant for vaccination and will be testing this hypothesis as well as mechanisms that lead to viral control over the next couple of years. <p >Aging and Immunity: The study of the impact of aging on CD4 T cell function at the naïve and memory stages has lead us to better understanding of fundamental aspects of T cell behavior in addition to providing important information about what vaccine approaches are most likely to be successful for the aged. Nature of CD4 Aging “Defects”. We have identified multiple levels at which aged naïve CD4 T cells are defective including initial early response to TcR triggering, IL-2 production, expansion and effector generation. The defects in helper function and in the 20 response of memory cells generated from aged naïve CD4 T cells are particularly dramatic. In recent studies we have recapitulated memory age-associated defects in recently generated memory cells in vitro (23). In vitro aged memory cells are markedly defective in production of particular cytokines, IL-4, IL-5 and IL-2, while others are little affected (IFNg, IL-10, TNF), suggesting the aging “defect” may be restricted to loss of potential to make certain CD4 T cell subsets, such as those responsible for help to B cells .We will pursue this hypothesis both in vitro and in vivo. <p >We have found that aged naïve CD4 T cells are in fact longer-lived than their naïve counterparts (23). We find that reduced expression of Bim, a proapoptotic protein, is responsible for this increase in lifespan and that the increase in lifespan is required for the development of aging defects. We are now investigating the factors that regulate Bim expression. <p >Enhancement by Inflammatory Cytokines. We have shown that the defective effector generation responses of naïve CD4 T cells from aged animals can be overcome by IL-2 and by proinflammatory cytokines, in particular a mix of IL-1, IL-6 and TNF (20,21). We want to determine the extent to which the inflammatory cytokines can reverse the heritable aging defects and restore functional memory generation. We have developed in vitro models to test the generation of effectors and memory. In these models we are evaluating TLR agonists for their ability to restore aged naïve CD4 responses to peptide-pulsed derived dendritic cells (DC). Pre-incubation of DC with many TLR agonists, enhances expansion of the responding aged naïve CD4 T cells via a mechanism dependent on IL-6 that acts in part by increasing survival of the developing effector population. We plan to use this model to identify the extent of the rescue and what pathways and mechanisms contribute with the ultimate goal of evaluating whether specific TLR stimulation or stimulation of specific pathways might improve the response of the elderly to vaccines. We want to see if we can reproduce this model with human naïve CD4 T cells and DC derived from peripheral blood and if TLR agonists can also enhance those responses. <p >
Governor Paul Cellucci Chair in Neuroscience Research
Project 1: Dervelop RNA-based therapies for frontotemporal dementia (FTD) and related disroders. Project 2: Study pathogenic mechanisms of FTD and related disorders in mouse models.
Our lab uses a combination of molecular, cellular, genetic, and behavioral approaches to further dissect the pathogenic mechanisms of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis with a focus on mutant CHMP2B, progranulin and C9ORF72. We will identify common underlying pathways as potential targets for therapeutic interventions.
Joy McCann Professor for Women in Medicine
A postdoc position is available to study circadian rhythms in Drosophila. Contact Patrick Emery (patrick.emery@umassmed.edu).
Biological clocks play an essential role in the temporal organization of animal physiology and behavior. We combine the powerful genetics of Drosophila with molecular, cell culture and behavioral approaches to obtain a comprehensive view of the mechanisms regulating circadian clocks and one of their critical output: sleep. We also now study the mechanisms enabling marine organisms to anticipate tides. Indeed, we have developed a model organism to study circatidal rhythms: Parhyale hawaiensis. Rotation projects could for example focus on characterizing new candudate post-transcriptional regulators of circadian rhythms, the role of glial genes in the control of sleep, or studying the molecular mechanisms of circatidal clocks.
Dr. Henninger is a vascular neurologist with research interest in the neurobiology of axonal injury associated with traumatic brain injury and its contribution to functional outcome.
A postdoctoral position is available to study in this laboratory. Contact Dr. Rogaev for additional details.
Additional information about lab rotations within the CPHR program can be found athttp://www.umassmed.edu/cphr/program/rotations.aspx
Higgins Family Professor in Neuroscience
Potential Rotation Projects Project #1: Molecular Mechanisms in the Pathogenesis of Neurodegenerative Disease. The student can select projects emphasizing either molecular mechanisms of huntingtin in trafficking in neurons or receptor stimulated effects on gene expression in neurons. Techniques include: Generation of fusion proteins, raising antisera Preparation of organelles Immunocytochemistry, light microscopy and electron microscopy Immunoprecipitation methods PCR Protein separation techniques, gel electrophoresis, immunoblotting Autoradiography
Arthur F. Koskinas Chair in Neuroscience
Many rotation projects are available so please inquire.
Postdoctoral Fellow Applications are being accepted for one position. A position is available to develop Cys2His2 zinc finger proteins (ZFPs) for the treatment of monogenic disorders. This project will focus on the creation of ZFPs with novel DNA-binding specificity to recognize sequence elements within genomic loci of therapeutic interest. In collaboration with other laboratories, we will evaluate the activity of these ZFP-based gene therapy reagents in vitro and in vivo in relevant disease models. Applicants will also have the opportunity to learn to apply Cas9 and Cas12a editing systems in vivo.
Potential Rotation Projects Improving the Precision of CRISPR/Cas9 nucleases for gene therapy applications: We are working to improve the precision of the CRISPR/Cas9 system to generate nucleases that will cleave at only a single site in the genome. These engineering efforts focus on increasing the DNA-editing precision of Cas9 and using protein engineering to introduce new properties into the nuclease. Much of this work is now transitioning to the use of Cas9 (and Cas12a) protein-RNA complexes. These modified nucleases will then be applied to patient derived cell-culture systems for the targeted repair or inactivation of disease-causing alleles. With the eventual goal of creating therapeutics for Sickle Cell Disease, beta-Thalassemia, HIV, Limb Girdle Muscular Dystrophy, Hermansky Pudlak Syndrome and other monogenic disorders. ex vivo genome editing in CD34+ HSPCs: We are developing improved Cas9 proteins for delivery ex vivo into CD34+ HSPCs for therapeutic application to sickle cell disease and beta-thalassemia. The goal is to modify the hematopoietic stem cells of a patient to complement the loss of function of the beta-globin gene and then return these cells to the patient through an autologous transplant. Development of Cys2His2 Zinc fingers proteins (ZFPs) as targeted therapeutics: We are developing artificial ZFPs for the regulation of target genes to change their gene expression profiles for therapeutic applications.
Richard M. Haidack Professor in Medicine
We are looking for motivated postdoctoral researchers. Send in your application and get in touch today!
- AAV gene therapy for genetic diseases - Therapeutic genome editing - RNA-based approaches to treating genetic diseases - Interactions between AAV vector and host cell - AAV vector capsid engineering
Dr. John Meyers Professor in Primary Care Medicine
Population and Quantitative Health Sciences
Healthcare Delivery and Population Sciences at UMass Chan - Baystate
Worcester Foundation for Biomedical Research Chair I
Susan D Moffatt-Bruce MD, PhD, FRCSC, MBOE, MBA,FACS
Joseph D. Early Chair in Biomedical Research